Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
1
of
13
Reviewer:
John
Doherty
ReRegistration
Branch
III,
HED
(
7509C)
Secondary
Reviewer:
Jess
Rowland
Science
Information
Management
Branch,
HED
(
7509C)

TXR
#
0050236
DER
for
a
Special
Non­
Guideline
Study
with
Human
Volunteers
Study
Type:
Special
Non­
Guideline
Cholinesterase
Study
with
Human
Volunteers.

DP
Barcode
No.:
D277372
PC
Code:
058001
Submission
No.:
S602411
Test
Material:
Azinphos
methyl
(
purity:
89.2
to
91.6%,
batch
number
703­
0139).

Citation:
P.
McFarlane
and
S.
Freestone,
"
A
Randomized
Double
Blind
Placebo
Controlled
Study
with
Azinphos­
Methyl
to
Determine
the
No
Effect
Level
on
Plasma
and
RBC
Cholinesterase
Activity
After
Repeated
Doses."
Inveresk
Research,
Study
No.:
ICR
013580,
April
15,
1999.
MRID
No.:
45476101
Sponsor:
Bayer
Corporation,
17745
South
Metcalf,
Stilwell,
KS
66085­
9104.

In­
Life
Phase:
March
2,
1999
to
April
15,
1999.

Executive
Summary:
In
this
special
28­
day
dosing
study
(
MRID
No.:
45476101)
with
human
subjects
(
males
only),
a
group
of
4
volunteers
were
dosed
as
placebo
(
lactose)
and
a
group
of
8
volunteers
were
dosed
with
0.25
mg/
kg/
day
of
azinphos
methyl
(
89.1%
to
91.6%
purity)
for
28
consecutive
days.
Dosing
was
orally
by
capsule
and
the
subjects
were
housed
in
a
clinic
throughout
the
dosing
period.
The
subjects
were
monitored
for
reactions
and
samples
of
their
blood
were
taken
at
predose
(
8
times)
and
daily
throughout
the
dosing
period.
On
some
days,
a
blood
sample
was
taken
both
prior
to
administering
the
dose
and
4
hours
after.
The
blood
was
separated
and
assessed
for
both
plasma
cholinesterase
(
ChE)
and
red
blood
cell
acetylcholinesterase
(
RBC
AChE).
In
addition,
hematology,
clinical
chemistry
and
urinalysis
were
evaluated
as
well
as
blood
pressure
and
ECG.
Systemic
Effects.
There
were
no
reactions
to
treatment
and
blood
pressure
and
ECG
parameters
were
not
affected.
Eight
of
the
12
volunteers
were
noted
to
have
symptoms
of
a
viral
infection
and
some
were
treated
with
paracetamol.
This
was
not
considered
to
affect
the
interpretation
of
the
study.
Cholinesterase
assessments.
The
plasma
ChE
in
IU/
mL
for
the
baseline
(
mean
"
the
standard
deviation)
was
6965"
1327
(
19%)
for
the
placebo
group
(
4
subjects)
and
5307"
1048
(
20%)
for
the
azinphos
methyl
treated
group
(
8
subjects)
meaning
that
the
azinphos
methyl
group
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
2
of
13
was
already
24%
less
prior
to
test
material
administration.
The
RBC
AChE
in
IU/
mL
for
the
baseline
was
10933"
255
("
2.3%)
for
the
placebo
group
and
11049"
478
(
4.3%)
for
the
azinphos
methyl
treated
group
prior
to
dosing.
The
mean
values
and
variance
are
as
would
be
expected
for
assessment
of
plasma
ChE
and
RBC
AChE
from
human
subjects.
The
postdosing
group
mean
data
were
compared
three
ways
in
an
effort
to
see
if
azinphos
methyl
caused
inhibition
of
either
plasma
ChE
or
RBC
AChE.
Neither
comparison
of
the
group
mean
for
the
dosed
group
with
i.
the
placebo
group
at
each
time
interval
or
ii.
the
dosed
groups
baseline
mean
(
the
most
appropriate
method)
indicated
inhibition
of
either
plasma
ChE
or
RBC
AChE.
In
particular,
the
maximum
decrease
in
plasma
ChE
was
only
6%
and
the
maximum
decrease
for
RBC
AChE
was
9%
(
which
occurred
only
on
one
day)
when
compared
to
the
baseline
mean.
Also,
samples
taken
4
hours
after
dosing
on
several
occasions
did
not
indicate
inhibition.
In
conclusion,
a
dose
of
0.25
mg/
kg/
day
of
azinphos
methyl
for
28
days
did
not
result
in
either
clinical
symptomology
or
inhibition
of
either
plasma
ChE
or
RBC
AChE
in
human
males.
The
NOAEL
is
0.25
mg/
kg/
day.

Classification:
Classification
of
this
study
is
RESERVED
pending
establishment
of
an
Agency
policy
for
classification
of
studies
using
human
subjects.

Compliance:
A
Combined
Good
Clinical
Practice
(
CPMP/
ICH/
135/
95)
for
treatment
of
human
subjects
and
a
OECD
Good
Laboratory
Practice
statement
was
provided
(
dated
August
3,
1999).
A
Statement
of
Data
Confidentiality
(
no
claim)
was
also
provided
(
dated
August
13,
1999).
Information
on
the
volunteer
consent
form
and
other
aspects
of
the
ethical
treatment
of
the
subjects
such
as
the
study
being
conducted
in
accordance
with
the
Declaration
of
Helsinki,
as
amended
in
1975,
1983,
1989
and
1996
were
provided.

A.
Study
Constants
and
Materials
1.
Test
Material:
Chemical:
Azinphos
methyl
Chemical
name:
S­(
3,4­
dihydro­
4­
oxobenzo[
d]­
1,2,3)­
triazin­
3­
ylmethyl)
O,
O­
dimethyl
phosphordithioate
Batch:
703­
0139
Purity:
89.2%
to
91.6%
Structure:
No
electronic
structure
available.
CAS
Number:
86­
50­
0.
Description:
Granulated
powder.
Supplier:
Bayer
Corporation
2.
Vehicle
of
Placebo:
Chemical:
Lactose
Purity:
No
information
provided.
Standard
stock
preparation.
Supplier:
J
M
Loverage,
Company
Batch
28811
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
3
of
13
3.
Test
Subjects:
Species:
Human
volunteers­
all
males
Race:
All
Caucasian
Age:
Criteria
for
inclusion
in
the
study
was
to
be
between
18
and
50
years
of
age.
The
mean
age
"
the
standard
deviation
of
the
placebo
group
was
35.3"
9.5
years
and
was
29.3"
9.6
years
for
the
group
dosed
with
azinphos
methyl.
Body
Weight:
61.8
to
90.4
kg.
Housing:
From
the
day
before
the
first
dose
until
24
hours
after
receiving
the
last
dose
the
subjects
resided
in
the
clinic
and
remained
under
constant
medical
and
nursing
supervision
and
received
a
standardized
diet.

Pages
19
to
22
of
the
study
report
describe
many
details
for
the
criteria
that
must
be
met
to
be
included
in
this
study.
Each
subject
was
given
a
screening
examination
to
assure
that
there
were
no
medical
reasons
for
exclusion.
In
general,
only
individuals
in
good
health
and
not
on
drugs
(
prescription
or
otherwise),
non­
smokers
and
capable
of
communicating
with
the
medical
staff
were
selected.
Objections
from
the
subjects
personal
physician
also
was
cause
to
preclude
a
persons
participation
in
the
study.
Agricultural
workers
and
pesticide
applicators
or
persons
exposed
to
an
anti­
cholinesterase
within
a
month
of
the
dosing
were
not
eligible.
During
the
study,
no
alcohol
or
caffeine
or
other
medications
were
allowed.
Note:
During
the
study
several
of
the
subjects
received
paracetamol
to
control
headache
and
viral
symptoms,
also,
one
subject
received
antibiotics.
HED
does
not
consider
that
either
treatment
with
paracetamol
or
the
antibiotics
would
compromise
the
study.

4.
Study
Protocol:
Table
1
illustrates
the
study
protocol.

Group
Number
of
Subjects
Assessments
Placebo
4
males
0.25
mg
azinphos
methyl
8
males
­
General
clinical
exam
(
self
reporting
of
any
possible
symptoms).
­
Systolic
and
diastolic
blood
pressure
just
prior
to
each
dose.
­
Electrocardiogram
(
12
lead),
Hematology
and
Clinical
Chemistry
and
Urinalysis:
prior
to
dosing
and
on
days
1,
7,
14,
21
and
28.
­
Plasma
ChE
and
RBC
AChE
assessments
­
on
screening
days
­
14,
­
12,
­
10,
­
8,
­
6,
­
4
and
­
1;
and
then
daily
after
dosing
with
special
assessments
on
days
on
days
1,
2,
3,
4,
5,
7,
10,
14,
17,
21,
24
and
28
when
two
blood
samples
were
taken
to
include
sampling
before
each
dose
and
4
hours
after
the
dosing
5.
Rationale
for
Dose
Level
Selection.
The
dose
level
of
0.25
mg/
kg/
day
was
selected
based
on
the
results
of
animal
studies
and
an
earlier
study
with
human
subjects
that
indicated
that
this
would
be
a
NOAEL.
for
inhibition
of
plasma
and
RBC
cholinesterase.

6.
Dosing.
Each
subject
was
dosed
by
capsule
containing
either
the
placebo
(
lactose)
or
azinphos
methyl
approximately
5
minutes
after
breakfast.
Table
3
(
page
38
of
the
study
report,
copy
attached)
shows
the
amount
in
mg
of
placebo
or
azinphos
methyl
actually
given
to
each
subject
on
each
day.

7.
Statistics:
The
data
were
analyzed
by
the
SAS
(
v6.07)
program.
This
system
produced
all
summary
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
4
of
13
tables
and
data
listings.
The
study
report
(
page
31)
discusses
the
use
of
Retrospective
Power
Calculation
to
detect
clinically
relevant
differences
if
the
study
was
repeated.

The
repeated
measures
ANOVA
model
was
used
for
analysis
of
percentage
change
from
baseline
plasma
and
RBC
cholinesterases
using
the
pooled
baseline
values
as
covariate.
This
was
done
by
comparing
the
goodness
of
fit
statistics
(
Akaike's
Information
Criterion
and
Schwart'z
Bayestan
Criterion)
for
both
models
including
and
excluding
the
pooled
baseline
value.
Table
M1.1.1
(
pages
491
to
501)
presents
the
results
of
the
statistical
tests.

Specific
Methods
and
Results
1.
Assessment
for
clinical
reactions.

All
subjects
remained
on
the
study
for
the
scheduled
time.
Comments
on
the
general
health
and
adverse
events
or
reactions
that
may
possibly
be
related
to
treatment
for
each
subject
are
illustrated
in
Table
2.
Note:
During
the
dosing
period
the
investigators
were
blind
to
whether
or
not
the
subject
actually
received
azinphos
methyl
and
they
made
their
determination
regarding
possibly
treatment
related
effects
based
on
the
symptoms
only.

Table
2.
Individual
subject
analysis
for
adverse
effects.
.

#
General
Condition
and
Possible
Reactions
HED
Conclusion
Placebos
1
4
adverse
events.
Viral
illness
on
day
27.
Headache
on
day
27
(
attributed
to
the
environment),
myalgia
on
day
19
and
mouth
dryness
on
day
27.
.
Subject
did
not
receive
azinphos
methyl.

5
13
adverse
events.
Viral
illness.
Chest
pain
on
days
7
and
9,
rhinitis
day
17
),
rash
on
day
11
and
pruritus
on
day
11,
elevated
ALT
from
day
­
14
to
day
28,
headache
on
day
14,
16,
18,
24,
26,
The
headache
and
other
symptoms
were
treated
with
paracetamol
and
attributed
to
the
ward
environment
or
virus.
Subject
did
not
receive
azinphos
methyl.

8
0
adverse
events.

12
0
adverse
events.

Azinphos
Methyl
Treated
2
14
adverse
events.
Both
pre
and
post
dose
headaches
(
on
days
­
2,
3,
8,
21,
23,
27
and
28).
Treated
with
paracetamol
and
attributed
to
the
environment
and
a
viral
illness.
Not
related
to
treatment.

3
2
adverse
events.
Headache
(
treated
with
paracetamol)
on
day
1
and
rhinitis
on
day
14
and
thought
to
be
related
to
a
viral
illness.
Not
related
to
treatment.
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
5
of
13
#
General
Condition
and
Possible
Reactions
HED
Conclusion
4
4
adverse
events.
Nausea
thought
to
be
related
to
the
diet.
Headache
(
day
11)
rhinitis
and
coughing
thought
to
be
related
to
viral
illness.
Not
related
to
treatment.

6
1
1
adverse
events.
Dietary
related
gastrointestinal
symptoms
and
headache
(
intermittent)
treated
with
paracetamol.
Not
related
to
treatment.

7
5
adverse
events.
Viral
illness
related
to
mouth
dryness
and
coughing
treated
with
paracetamol.
Raised
ALT
and
GGT
Not
related
to
treatment.

9
8
adverse
events.
Diet
related
indigestion,
back
pain
and
raised
AST.
Not
related
to
treatment.

10
7
adverse
events.
Viral
illness
related
to
rhinitis
and
coughing
and
headache
(
also
attributed
to
the
ward
conditions).
Mouth
ulcer
and
facial
pain
treated
with
ibuprofen
and
amoxycillin.
Not
related
to
treatment.

11
2
adverse
events.
Viral
illness
thought
to
be
related
to
lymphadenopathy
and
rhinitis
treated
with
paracetamol.
Not
related
to
treatment.

Overall
Comment
on
treated
subjects.
Much
the
same
symptoms
that
were
reported
in
the
placebo
group
without
indications
of
increased
intensity
were
also
reported
in
the
group
dosed
with
azinphos
methyl.

Not
all
aliments
that
a
subject
reported
are
mentioned
above
since
some
were
very
obviously
not
recognized
as
being
response
to
treatment
with
an
organophosphate.
For
example,
skin
lesions
are
not
mentioned.

It
is
concluded
that
none
of
the
subjects
dosed
with
azinphos
methyl
developed
symptoms
indicative
of
organophosphate
poisoning.
Most
of
the
subjects
(
i.
e.
8
of
the
12
on
the
study)
were
reported
to
have
developed
a
viral
illness
with
some
subjects
apparently
having
more
viral
related
symptoms
than
others.
It
should
also
be
noted
that
there
was
no
increase
in
the
severity
of
the
symptoms
in
the
subjects
when
compared
with
the
controls
and
the
severity
was
graded
as
1
or
2
(
low
degree).

Another
apparent
cause
of
adverse
events
was
discomfort
related
to
being
confined
in
the
clinic.
This
is
understandable.

2.
Specific
tests
Blood
pressure
and
heart
rate.
There
were
no
changes
in
blood
pressure
or
heart
rate
in
response
to
azinphos
methyl
administration.

ECG.
There
were
no
clinically
significant
effects
on
the
ECG
patterns
of
the
subjects
on
this
study.

3.
Clinical
Chemistry
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
6
of
13
Hematology.
Appendix
K
(
pages
K1
to
K24
in
Volume
2)
indicates
that
hemoglobin,
red
blood
cells,
hematocrit.
mean
cell
hemoglobin
concentration,
mean
cell
volume,
white
blood
cells
count
(
including
neutrophils,
lymphocytes,
monocytes.
eosinophils.
basophils,
LUC
(
large
unclassified
cells),
and
platelets
were
assessed.

There
were
no
meaningful
effects
of
azinphos
methyl
on
these
parameters.

Clinical
Chemistry.
Appendix
L
(
pages
L1
to
L23
in
Volume
2)
indicates
that
urea,
glucose.
AST
(
aspartate
aminotransferase),
ALT
(
alanine
aminotransferase),
LDH
(
lactate
dehydrogenase),
sodium,
potassium,
chloride,
TP
(
total
protein),
albumin,
T.
Bi
(
total
bilirubin),
GGT
(
gamma
glutamyl
transferase)
and
creatinine
were
assessed.

There
were
some
increases
in
AST
and
ALT
that
resolved
themselves
and
were
not
considered
to
be
related
to
treatment.
For
example
they
were
transient
(
self
resolving)
and
considered
to
be
within
normal
variation.

4.
Cholinesterase
Assessment.

General
Preparation
and
Separation
and
Basic
Assay.

Blood
samples
(
4.5
mL)
were
taken
by
venipuncture
each
day
at
screening,
on
days
­
14,
­
12,
­
10,
­
8,
­
6,
­
4,
­
2,
and
­
1
(
before
dosing)
and
on
days
1,
2,
3,
4,
5,
6,
7,
10,
14,
17,
21,
24
and
28
postdosing.
Page
26
of
the
study
report
states
that
on
postdosing
days
samples
were
taken
prior
to
dosing
and
4
hours
postdosing.
However,
the
individual
subject
data
tables
in
Appendix
M
of
the
study
report
present
data
to
indicate
that
blood
cholinesterase
was
measured
every
day
of
the
study.
The
samples
were
collected
in
tubes
containing
EDTA
and
centrifuged
to
separate
the
plasma
from
the
RBCs.
These
were
shipped
to
IR
laboratory
at
Elphinstone
Research
Centre
on
wet
ice
and
assayed
the
same
day.
The
actual
time
between
sample
collection
and
assay
time
was
not
stated
and
may
have
been
different
for
each
day
and
there
may
have
been
different
interval
times
for
each
subject.
.
Plasma
ChE
and
RBC
AChE
was
assessed
following
the
SOP/
CLC/
043
using
an
Hitachi
Analyzer.
This
analyzer
utilizes
acetylthiocholine
as
the
substrate
and
is
a
modification
of
Ellman's
original
method.

Plasma
ChE
and
RBC
AChE
baseline
values
and
variability
of
the
data.

A
general
summary
of
the
plasma
ChE
and
RBC
AChE
for
the
baseline
data
is
presented
in
Table
3.

Table
3.
Mean
baseline
plasma
ChE
and
RBC
AChE
data.
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
7
of
13
Plasma
ChE
(
IU/
L)
Placebo
Group
AZM
Group
RBC
AChE
(
IU/
L)
Placebo
Group
AZM
Group
6965"
1327
("
19%)
5307"
1048
("
20%)
(
range
5722
to
8757)
(
range
3366
to
6840)
10933"
255
("
2.3%)
11049"
478
("
4.3%)
(
range
10663
to
11196)
(
range
10394
to
11854)
Baseline
Values
Note:
There
is
a
24%
difference
between
the
placebo
and
treated
group
before
the
start
of
AZM
dosing.
This
is
likely
due
to
the
subjects
with
the
two
highest
plasma
ChE
values
are
in
the
placebo
group
and
the
subject
with
the
lowest
is
in
the
AZM
group.

The
19%
and
20%
standard
deviation
shows
poor
precision.
The
placebo
and
treated
group
are
very
comparable
prior
to
dosing.

There
is
good
precision
since
the
standard
deviations
are
small
(
2.3%
and
4.3%)

5739"
1071
("
19%)
5256"
1325
("
25%)
6285"
1199("
19%)
6402"
1129("
18%)
5715"
757
("
13%)
11595"
1323("
11%)
12810"
1013("
8%)
12712"
961
("
8%)
11524"
1296
("
11%)
11387"
1280
("
11%)
Comparison
of
the
baseline
values
with
the
acute
study
(
a)

Similarly
large
standard
deviations
were
obtained
in
both
studies.
The
standard
deviations
for
the
subchronic
study
are
smaller
than
for
the
acute
study
meaning
that
there
was
better
precision
in
the
acute
study.

(
a).
Refer
to
MRID
No.:
44786901
for
the
acute
study
with
humans
and
azinphos
methyl.
The
acute
study
had
four
dose
levels
for
males
and
the
baseline
is
presented
for
each
dose
group.
There
were
12
subjects
in
the
placebo
group
for
the
acute
study
and
7
subjects
in
each
group
dosed
with
AZM.
This
compares
with
only
4
subjects
in
the
placebo
groups
and
8
subjects
in
the
dosed
group
for
the
28
day
study.

Table
3
shows
that
the
standard
deviation
is
19
to
20%
of
the
mean
for
the
plasma
ChE
data
(
based
on
4
subjects).
This
compares
with
a
13­
25%
obtained
in
the
previous
acute
study
with
azinphos
methyl
in
human
subjects.
The
standard
deviation
for
RBC
AChE
was
only
2.3
to
4.3%
for
the
baseline
values
which
indicates
good
precision.
However,
throughout
the
course
of
the
study
the
standard
deviations
for
RBC
AChE
means
were
as
high
as
15%.
(
i.
e
see
day
1for
the
placebo
group
at
4
hours
after
dosing
in
Appendix
M,
Table
M2.2
also
shown
in
Table
4
below).

There
is
much
variation
between
the
subject
with
the
lowest
(
3366"
100
IU/
L)
baseline
plasma
ChE
and
the
highest
(
8757"
442
IU/
L)
but
these
recordings
are
within
the
normal
range
for
human
plasma
ChE.

Assessment
for
Inhibition
of
Plasma
ChE
and
RBC
AChE
Based
on
Group
Mean
Data.

Table
4
illustrates
group
mean
data
for
plasma
ChE
and
RBC
AChE
assessments
at
selected
time
intervals.
The
potential
for
azinphos
methyl
to
inhibit
both
plasma
ChE
or
RBC
AChE
was
assessed
three
ways.

i.
by
comparison
of
the
day
to
day
value
for
the
azinphos
methyl
treated
group
with
the
same
day
value
for
the
placebo
group.
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
8
of
13
Since
plasma
ChE
for
the
group
that
was
to
receive
the
azinphos
methyl
was
already
24%
less
than
the
placebo
before
the
start
of
dosing,
all
values
were
remained
about
17
to
24%
less
than
the
placebo
throughout
dosing.
Thus,
there
was
no
inhibition.
The
lowest
decease
for
RBC
AChE
was
only
3%
but
many
values
were
higher
for
the
dosed
group
relative
to
the
placebo
group.

ii.
by
comparison
of
the
same
day
predosing
cholinesterase
data
with
the
cholinesterase
data
obtained
4
hours
after
dosing.

The
maximum
difference
was
9%
decrease
for
the
10
hour
sample
but
his
was
not
sustained
and
the
4
hour
sample
was
low
for
the
placebo
(
5%,
i.
e.
10346/
10933
=
0.946
or
5%)
group
also
indicating
an
experimental
variation
and
not
true
inhibition.

iii.
by
comparison
of
the
azinphos
methyl
group
data
obtained
each
day
with
the
predosing
baseline
value.

Table
4
shows
that
at
day
10
the
4
hour
postdosing
sample
was
7%
lower
than
the
predosing
assessment.
However,
the
placebo
group
was
also
8%
lower
after
4
hours.
Thus,
the
7%
decrease
is
not
considered
inhibition.

Neither
of
these
three
methods
resulted
in
an
indication
that
azinphos
methyl
inhibited
either
plasma
ChE
or
RBC
AChE
at
any
time
interval.

Assessment
of
plasma
ChE
and
RBC
AChE
inhibition
based
on
analysis
of
individual
subjects.

Table
5
illustrates
the
plasma
ChE
and
RBC
AChE
data
for
each
subject
on
the
study.

Plasma
ChE.
Table
5
shows
that
in
the
placebo
group
plasma
ChE
can
be
reduced
to
86%
and
elevated
to
110%
above
the
baseline
obtained
by
repeated
samplings
both
before
and
during
the
dosing
period.
Table
5
also
shows
that
for
the
subjects
dosed
with
azinphos
methyl
their
predosing
baseline
can
be
as
low
as
84%
(
subject
#
11)
of
his
baseline
mean.
During
the
dosing
period,
one
subject
(#
9)
in
the
azinphos
methyl
group
was
reduced
to
as
much
as
83%
of
his
baseline
mean.
Thus,
there
is
no
indication
of
inhibition
of
plasma
ChE
when
the
individual
subject
data
are
evaluated.
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
9
of
13
Table
4.
Comparison
of
Plasma
ChE
and
RBC
AChE
in
the
Placebo
and
Azinphos
Methyl
Dosed
Groups
Based
on
Group
Mean
Data.

Day
(
a)
Plasma
ChE
(
IU/
L)
Placebo
0.25
AZM
%
Diff.
(
b)
%
Diff.(
c)
RBC
AChE
(
IU/
L)
Placebo
0.25
AZM
%
Diff.
(
b)
%
Diff
(
c)

Baseline(
e)
6965"
1327
5307"
1048
­
24%
­­
10933"
225
11409"
478
+
4%

1
6532"
1153
4980"
965
­
24%
­
6%
6465"
1170
4985"
988
­
24%
­
6%
(~)
(
d)
(~)
10738"
699
11220"
811
+
5%
~
11681"
1723
11683"
803
~
+
2%
(+
9%)
(+
4%)

4
6669"
1258
5219"
959
­
22%
~
6420"
1502
5139"
957
­
20%
­
3%
(­
4%)
(~)
9543"
956
11256"
791
+
18%
~
10742"
812
11170"
928
+
4%
­
2%
(+
13%)
(~)

8
6440"
1363
5098"
989
­
21%
­
4%
10706"
539
11151"
610
+
4%
­
2%

10
6768"
1546
5323"
960
­
17%
~
6733"
1286
5250"
970
­
22%
~
(~)
(~)
11263"
643
11233"
1139
~
~
10346"
1323
10399"
733
~
­
9%
(­
8%)
(­
7%)

12
6452"
1288
5095"
1080
­
21%
­
4%
11770"
1499
11393"
1163
­
3%
~

16
6545"
1195
5208"
1010
­
20%
­
2%
10953"
539
10992"
515
~
­
4%

21
7013"
1425
5437"
1010
­
22%
+
2%
6791"
1179
5432"
998
­
20%
+
2%
(
3%)
(~)
10587"
224
10909"
728
+
3%
­
4%
10383"
339
11552"
1363
+
11%
~
(­
2%)
(+
6%)

24
7172"
1617
5477"
931
­
24%
+
3%
6989"
1224
5637"
1079
­
19%
+
6%
(
3%)
(+
3%)
11555"
1297
11425"
898
~
~
11620"
1715
11391"
675
­
2%
~
(~)
(~)

28
6819"
1537
5512"
964
­
19%
+
4%
6752"
1418
5560"
888
­
18%
+
5%
(~)
(~)
11381"
1043
11488"
694
~
~
11428"
525
11326"
895
~
~
(~)
(~)

Data
are
from
Appendix
M
Tables
M2.1(
plasma
ChE)
and
M2.2
(
RBC
AChE)
pages
M45
to
M56.
(
a)
Days
"
baseline",
1,
4,
8,
10,
12,
16,
21,
24
and
28
were
selected
for
inclusion
in
this
table
to
show
representative
values.
Days
1,
4,
10,
21,
24
and
28
also
were
days
on
which
blood
samples
were
taken
before
the
azinphos
methyl
was
administered
and
4
hours
after
administration.
(
b)
The
percent
difference
between
the
mean
for
the
azinphos
methyl
dosed
group
and
the
mean
for
the
placebo
is
calculated
for
each
day.
(
c)
The
percent
difference
between
the
mean
for
the
azinphos
methyl
dosed
group
at
each
day
is
calculated
based
on
the
mean
baseline
value
for
the
azinphos
methyl
group.
(
d)
The
value
for
plasma
ChE
or
RBC
AChE
obtained
prior
to
dosing
is
compared
with
the
value
obtained
4
hours
after
dosing.
(
e).
The
baseline
is
the
mean
"
the
standard
deviation
for
the
value
of
the
cholinesterase
made
on
days
­
14,
­
12.­
10,
­
8,
­
6,
­
4,
­
2
and
­
1.
Each
days
predosing
value
is
presented
in
Tables
M2.1
and
M2.2.
~
indicates
that
the
value
was
essentially
the
same
as
the
baseline.
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
10
of
13
Table
5.
Individual
subject
analysis.
The
baseline
mean
"
the
standard
deviation
is
presented
together
with
the
lowest
and
the
highest
reading
over
the
course
of
the
28
day
dosing
period.

Su
bje
ct
Nu
mb
er
Plasma
ChE
(
IU/
L)
Baseline
Data
Dosing
Data
RBC
AChE
(
IU/
L)
Baseline
Data
Dosing
Data
Placebos
1
Mean:
6258"
264
Low:
5827
(
93%)
Low:
5590
(
89%)
High:
6692
(
107%)
High:
6813
(
109%)
Mean:
10867"
1141
Low:
9455
(
87%)
Low:
9104
(
84%)
High:
12789
(
118%)
High:
12606
(
116%)

5
Mean:
8757"
442
Low:
8215
(
94%)
Low:
7670
(
88%)
High:
9390
(
107%)
High:
9666
(
110%)
Mean:
11004"
1502
Low:
9144
(
83%)
Low:
8696
(
79%)
High:
13699
(
125%)
High:
12914
(
117%)

8
Mean:
5722
Low:
5384
(
94%)
Low:
4927
(
86%)
High:
6092
(
106%)
High:
6099
(
107%)
Mean
10663
Low:
9663
(
91%)
Low:
9074
(
85%)
High:
12794
(
120%)
High:
13719
(
129%)

12
Mean:
7121
Low:
6930
(
97%)
Low:
6195
(
87%)
High
:
7501
(
105%)
High:
7612
(
107%)
Mean:
11196
Low:
10096
(
90%)
Low:
8672
(
77%)
High:
11855
(
106%)
High:
13570
(
121%)

Overall
comment
on
placebos.
Plasma
may
be
as
low
as
86%
and
as
high
as
110%
of
baseline,
RBC
may
be
as
low
77%
and
as
high
as
129%
of
baseline.

Azinphos
Methyl
Treated
2
Mean:
5684
Day
11:
5589
(
98%)
Low:
5348
(
94%)
Low:
5140
(
90%)
High:
6093
(
107%)
High:
6625
(
117%)
Mean:
10394
Day
11:
10111
(
97%)
Low:
9189
(
88%)
Low:
9228
(
89%)
High:
11162
(
107%)
High:
11815
(
114%)
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
11
of
13
Su
bje
ct
Nu
mb
er
Plasma
ChE
(
IU/
L)
Baseline
Data
Dosing
Data
RBC
AChE
(
IU/
L)
Baseline
Data
Dosing
Data
3
Mean:
4807
Day
11:
4979
(+
104%)
Low:
4625
(
96%)
Low:
4101
(
85%)

High:
5779
(
120%)
Mean:
11079
Day
11:
10247
(
92%)
Low:
10009
(
90%)
Low:
9017
(
81%)

High:
11242
(
101%)

4
Mean:
3366"
100
Day
11:
3744
(+
112%)
Low:
3185
(
95%)
Low:
3141
(
93%)

High:
6014
(
177%)
Mean:
11361"
2291
Day
11:
11494
(~)
Low:
9051
(
80%)
Low:
9290
(
82%)

High:
11996
(
106%)

6
Mean:
5639
Day
11:
6003
(
107%)
Low:
5434
(
96%)
Low:
5411
(
96%)

High:
6840
(
121%)
Mean:
11215
Day
11:
10781
(
96%)
Low:
9573
(
85%)
Low:
9054
(
81%)

High:
13071
(
117%)

7
Mean:
6209
Day
11:
6662
(
107%)
Low:
5972
(
96%)
Low:
5726
(
92%)

High:
6759
(
109%)
Mean:
10811
Day
11:
10444
(
97%)
Low:
9276
(
86%)
Low:
9436
(
87%)

High:
11998
(
111%)

9
Mean:
4914
Day
11:
4691
(
95%)
Low:
4682
(
95%)
Low:
4078
(
83%)

High:
5092
(
104%)
Mean:
11194
Day
11:
10425
(
93%)
Low:
9265
(
83%)
Low:
8533
(
76%)

High:
13385
(
120%)

10
Mean:
6840
Day
11:
6610
(
97%)
Low:
6358
(
93%)
Low:
5891
(
86%)

High:
6947
(
102%)
Mean:
10483
Day
11:
10852
(
104%)
Low:
9269
(
88%)
Low:
9668
(
92%)

High:
13895
(
133%)

11
Mean:
4998"
365
Day
11:
4794
(
96%)
Low:
4214
(
84%)
Low:
4362
(
87%)
Mean:
11854"
1269
Day
11:
11789
(~)
Low:
10341
(
87%)
Low:
9436
(
80%)
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
12
of
13
Su
bje
ct
Nu
mb
er
Plasma
ChE
(
IU/
L)
Baseline
Data
Dosing
Data
RBC
AChE
(
IU/
L)
Baseline
Data
Dosing
Data
High:
5602
(
112%)
High:
13881
(
117%)

Overall
Comment
on
treated
subjects.
There
was
no
indication
of
inhibition
of
either
plasma
ChE
or
RBC
AChE.
The
absolute
value
of
the
lowest
value
is
below
the
mean
is
about
the
same
as
the
absolute
value
as
the
higher
value
is
above
the
mean.

Data
are
from
Tables
M3
in
Appendix
M.
The
first
entry:
is
the
mean
of
the
8
baseline
assessments
"
the
standard
deviation.
The
standard
deviation
was
calculated
by
the
reviewer.
Not
all
baseline
entries
are
accompanied
by
the
standard
deviation.
The
high
and
low
values
are
those
that
occurred
following
dosing.
The
percentage
in
()
is
the
change
relative
to
the
baseline
for
that
individual.

RBC
AChE.
Table
5
shows
that
in
the
placebo
group,
RBC
ACHE
can
be
reduced
to
77%
(
subject
#
12)
of
the
baseline
mean
whereas
the
maximum
decrease
in
the
treated
group
was
76%
(
subject
#
9'
s
baseline
mean.
There
were
many
values
that
were
higher
than
the
mean
during
the
course
of
the
study.
For
example,
subject
#
9
which
had
the
largest
decrease
of
23%
on
day
14
also
had
a
value
that
was
20%
higher
than
the
baseline
mean.
The
graphs
of
this
individuals
cholinesterase
data
are
appended.
Thus,
there
is
no
indication
that
there
was
inhibition
of
RBC
AChE
based
on
individual
subject
data.

Analysis
at
day
11.
Based
on
the
review
of
a
similar
study
with
one
other
organophosphate
(
diazinon,
MRID
No.:
45184301),
the
inhibition
of
plasma
ChE
plateaued
at
approximately
day
11.
Thus,
data
from
day
11
are
presented
in
Table
5
since
if
there
was
inhibition
it
would
be
expected
to
have
been
evident
on
this
day.
The
eight
subjects
had
plasma
ChE
of
98%,
104%,
112%,
107%,
107%,
95%,
97%
and
96%
mean
and
RBC
AChE
of
97%,
92%,
~
100%,
96%,
97%,
93%,
104%
and
~
100%
of
the
predose
mean.
There
was
also
no
pattern
of
inhibition
at
later
days
that
would
indicate
that
the
time
to
plateau
for
azinphos
methyl
was
longer
than
for
diazinon.
Thus,
there
is
no
indication
of
biologically
meaningful
inhibition
in
any
of
the
subjects.

Discussion
and
Conclusions.

1.
Study
Author's
Conclusion.

The
study
author
(
page
56
of
the
study
report)
concluded
that
there
were
no
adverse
effects
of
azinphos
methyl
and
that
there
was
no
clinically
relevant
reductions
in
plasma
or
RBC
cholinesterase
at
a
dose
level
of
0.25
mg/
kg/
day
for
28
days.

2.
Discussion
and
Conclusion.
Azinphos­
Methyl/
1998
Special
28­
day
study
in
humans.

Page
13
of
13
The
reviewer
concurs
with
the
study
author
that
there
was
no
biologically
meaningful
inhibition
of
either
plasma
ChE
or
RBC
AChE
in
the
human
subjects
dosed
daily
for
28
days
with
0.25
mg/
kg
of
azinphos
methyl
by
oral
capsule.
There
were
also
no
indications
that
the
subjects
experienced
adverse
reactions
to
daily
administration
of
azinphos
methyl
for
28
days.

3.
Classification
and
Study
Deficiencies.

The
classification
of
this
study
is
being
reserved
until
the
Agency
formulates
a
policy
for
classifying
studies
with
human
subjects.

There
were
no
study
deficiencies
that
would
compromise
the
interpretation
of
the
study.
There
were
some
reporting
problems
in
that
some
critical
information
on
methods
and
procedures
were
scattered
in
Appendixes
of
the
study
and
not
in
the
study
methods
and
materials
section.
Also,
Table
3
of
the
study
report
was
found
to
be
misleading
in
that
it
does
not
specifically
state
that
the
placebo
group
was
dosed
with
lactose
since
only
a
weight
of
material
administered
was
given.
